Cross-selective Deoxygenative Coupling of Aliphatic Alcohols: Installation of Methyl Groups including Isotopic Labels by Nickel Catalysis.

Nickel-catalyzed cross-electrophile coupling reactions of two aliphatic alcohol derivatives remain a challenge. Herein, we report a nickel-catalyzed reductive methylation reaction of aliphatic mesylates with methyl tosylate. This reaction provides straightforward access to compounds bearing aliphatic methyl groups from alkyl alcohol derivatives. Isotopically labelled substrates and reagents can be employed in the reaction to provide perdeuterated and 13C-labelled products. This transformation can be achieved by employing stoichiometric Mn reductant or electrochemically. Additionally, mechanistic experiments show that alkyl iodides are key intermediates in the transformation which undergo a stereoablative reaction via radical intermediates.

The changing profile of infective endocarditis: A multi-year retrospective study for dentists.

BACKGROUND: Infective endocarditis (IE) has high morbidity and mortality and is often attributed to dental procedures. AIM: This study characterized variables related to paediatric IE in a paediatric hospital cohort. DESIGN: A retrospective review of medical records, from January 1, 2008, to January 1, 2020, to examine demographic, medical and dental history, and risk factors associated with children diagnosed with IE at Nationwide Children's Hospital. RESULTS: Of the 242 patients who were admitted with tentative IE diagnoses, 67 met the inclusion criteria: 46 (69%) had underlying cardiac conditions and 21 (31%) had not. One-third had an infection with S. aureus and viridans streptococci. Age was significantly associated with intracardiac devices in children with IE. Mean hospitalization was 25 days, and the mortality was 6 (9%); 41(61%) required surgery for causative defects, and 24 (32%) had dental consultation during admission. CONCLUSION: Although cardiac-related conditions were present in most cases, IE occurred in patients without cardiac factors.

Cannabis use as a potential mediator between childhood adversity and first-episode psychosis: results from the EU-GEI case-control study.

BACKGROUND: Childhood adversity and cannabis use are considered independent risk factors for psychosis, but whether different patterns of cannabis use may be acting as mediator between adversity and psychotic disorders has not yet been explored. The aim of this study is to examine whether cannabis use mediates the relationship between childhood adversity and psychosis. METHODS: Data were utilised on 881 first-episode psychosis patients and 1231 controls from the European network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) study. Detailed history of cannabis use was collected with the Cannabis Experience Questionnaire. The Childhood Experience of Care and Abuse Questionnaire was used to assess exposure to household discord, sexual, physical or emotional abuse and bullying in two periods: early (0-11 years), and late (12-17 years). A path decomposition method was used to analyse whether the association between childhood adversity and psychosis was mediated by (1) lifetime cannabis use, (2) cannabis potency and (3) frequency of use. RESULTS: The association between household discord and psychosis was partially mediated by lifetime use of cannabis (indirect effect coef. 0.078, s.e. 0.022, 17%), its potency (indirect effect coef. 0.059, s.e. 0.018, 14%) and by frequency (indirect effect coef. 0.117, s.e. 0.038, 29%). Similar findings were obtained when analyses were restricted to early exposure to household discord. CONCLUSIONS: Harmful patterns of cannabis use mediated the association between specific childhood adversities, like household discord, with later psychosis. Children exposed to particularly challenging environments in their household could benefit from psychosocial interventions aimed at preventing cannabis misuse.

Exploring the mediation of DNA methylation across the epigenome between childhood adversity and First Episode of Psychosis-findings from the EU-GEI study.

ABTRACT: Studies conducted in psychotic disorders have shown that DNA-methylation (DNAm) is sensitive to the impact of Childhood Adversity (CA). However, whether it mediates the association between CA and psychosis is yet to be explored. Epigenome wide association studies (EWAS) using the Illumina Infinium-Methylation EPIC array in peripheral blood tissue from 366 First-episode of psychosis and 517 healthy controls was performed. Adversity scores were created for abuse, neglect and composite adversity with the Childhood Trauma Questionnaire (CTQ). Regressions examining (I) CTQ scores with psychosis; (II) with DNAm EWAS level and (III) between DNAm and caseness, adjusted for a variety of confounders were conducted. Divide-Aggregate Composite-null Test for the composite null-hypothesis of no mediation effect was conducted. Enrichment analyses were conducted with missMethyl package and the KEGG database. Our results show that CA was associated with psychosis (Composite: OR = 1.68; p = <0.001; abuse: OR = 2.16; p < 0.001; neglect: OR = 2.27; p = <0.001). None of the CpG sites significantly mediated the adversity-psychosis association after Bonferroni correction (p < 8.1 × 10-8). However, 28, 34 and 29 differentially methylated probes associated with 21, 27, 20 genes passed a less stringent discovery threshold (p < 5 × 10-5) for composite, abuse and neglect respectively, with a lack of overlap between abuse and neglect. These included genes previously associated to psychosis in EWAS studies, such as PANK1, SPEG TBKBP1, TSNARE1 or H2R. Downstream gene ontology analyses did not reveal any biological pathways that survived false discovery rate correction. Although at a non-significant level, DNAm changes in genes previously associated with schizophrenia in EWAS studies may mediate the CA-psychosis association. These results and associated involved processes such as mitochondrial or histaminergic disfunction, immunity or neural signalling requires replication in well powered samples. The lack of overlap between mediating genes associated with abuse and neglect suggests differential biological trajectories linking CA subtypes and psychosis.

The Effects of Tranexamic Acid in Breast Surgery: A Systematic Review and Meta-Analysis.

BACKGROUND: Tranexamic acid (TXA) is used in trauma and surgical settings. Its role in reducing postoperative blood loss in breast surgery remains unclear. The primary objective of this study was to determine the effect of TXA on postoperative blood loss in breast surgery. METHODS: Searches of the PubMed, Ovid MEDLINE, Embase, CINAHL, and Cochrane Central Register of Controlled Trials databases were performed from inception to April 3, 2020. Inclusion criteria were any retrospective reviews, prospective cohort studies, and randomized controlled trials that administered TXA (topical or intravenously) in the context of breast surgery. Quality of studies were evaluated using the risk of bias in randomized trials tool and the risk of bias in nonrandomized studies of interventions tool. Data were pooled, and a meta-analysis was performed. RESULTS: In total, seven studies were included, representing 1226 patients (TXA, 632 patients; control, 622 patients). TXA was administered as follows: topically (20 mL of 25 mg/mL TXA intraoperatively; n =258 patients), intravenously (1 to 3 g perioperatively; n = 743 patients), or both (1 to 3 g daily up to 5 days postoperatively; n = 253 patients). TXA administration reduced hematoma formation in breast surgery (risk ratio, 0.48; 95% CI, 0.32 to 0.73), with no effect on drain output (mean difference, -84.12 mL; 95% CI, -206.53 to 38.29 mL), seroma formation (risk ratio, 0.92; 95% CI, 0.60 to 1.40), or infection rates (risk ratio, 1.01; 95% CI, 0.46 to 2.21). No adverse effects were reported. CONCLUSION: The use of TXA in breast surgery is a safe and effective modality with low-level evidence that it reduces hematoma rates without affecting seroma rates, postoperative drain output, or infection rates.

Immobilization of the Wrist After Dorsal Wrist Ganglion Excision: A Systematic Review and Survey of Current Practice.

BACKGROUND: Postoperative care after dorsal wrist ganglion (DWG) excision is highly varied. The effect of immobilization of the wrist on patient outcomes has not yet been examined. METHODS: A systematic review of the literature was performed to determine whether wrist immobilization after DWG surgical excision is beneficial. A survey of hand surgeons in Canada was performed to sample existing practice variations in current immobilization protocols after DWG excision. RESULTS: A systematic review yielded 11 studies that rigidly immobilized the wrist (n = 5 open excision, n = 5 arthroscopic excision, n = 1 open or arthroscopic excision), 10 studies that used dressings to partially limit wrist motion (n = 5 open, n = 5 arthroscopic), 1 study (open) that did either of the above, and 2 studies (arthroscopic) that did not restrict wrist motion postoperatively. This ranged from 48 hours to 2 weeks in open DWG excision and 5 days to 3 weeks in arthroscopic DWG excision. The survey of Canadian hand surgeons had a similarly divided result of those who chose to immobilize the wrist fully (41%), partially (14%), or not at all (55%). Most surgeons surveyed who immobilized the wrist postoperatively did so for 1 to 2 weeks. CONCLUSION: The systematic review and survey of Canadian hand surgeons reveal that hand surgeons are divided regarding the need to immobilize the wrist after DWG excision. In terms of functional outcome, there is no compelling data to suggest 1 strategy is superior. The time frame for immobilization when undertaken was short at 2 weeks or less.The systematic review is registered in the PROSPERO database (PROSPERO 2016:CRD42016050877).

Age acquired skewed X chromosome inactivation is associated with adverse health outcomes in humans.

Background: Ageing is a heterogenous process characterised by cellular and molecular hallmarks, including changes to haematopoietic stem cells and is a primary risk factor for chronic diseases. X chromosome inactivation (XCI) randomly transcriptionally silences either the maternal or paternal X in each cell of 46, XX females to balance the gene expression with 46, XY males. Age acquired XCI-skew describes the preferential selection of cells across a tissue resulting in an imbalance of XCI, which is particularly prevalent in blood tissues of ageing females, and yet its clinical consequences are unknown. Methods: We assayed XCI in 1575 females from the TwinsUK population cohort using DNA extracted from whole blood. We employed prospective, cross-sectional, and intra-twin study designs to characterise the relationship of XCI-skew with molecular and cellular measures of ageing, cardiovascular disease risk, and cancer diagnosis. Results: We demonstrate that XCI-skew is independent of traditional markers of biological ageing and is associated with a haematopoietic bias towards the myeloid lineage. Using an atherosclerotic cardiovascular disease risk score, which captures traditional risk factors, XCI-skew is associated with an increased cardiovascular disease risk both cross-sectionally and within XCI-skew discordant twin pairs. In a prospective 10 year follow-up study, XCI-skew is predictive of future cancer incidence. Conclusions: Our study demonstrates that age acquired XCI-skew captures changes to the haematopoietic stem cell population and has clinical potential as a unique biomarker of chronic disease risk. Funding: KSS acknowledges funding from the Medical Research Council [MR/M004422/1 and MR/R023131/1]. JTB acknowledges funding from the ESRC [ES/N000404/1]. MM acknowledges funding from the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. TwinsUK is funded by the Wellcome Trust, Medical Research Council, European Union, Chronic Disease Research Foundation (CDRF), Zoe Global Ltd and the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London.

A systematic review and meta-analysis of non-vitamin K antagonist oral anticoagulants vs vitamin K antagonists after transcatheter aortic valve replacement in patients with atrial fibrillation.

PURPOSE: Transcatheter aortic valve replacement (TAVR) is increasingly carried out in patients with aortic valvular conditions. Atrial fibrillation (AF) is a common comorbidity among patients undergoing TAVR. Despite this, there remains a paucity of data and established guidelines regarding anticoagulation use post-TAVR in patients with AF. METHODS: Four databases were searched from inception until 12 October 2021. A title and abstract sieve, full-text review and data extraction were conducted by independent authors, and articles including patients without AF were excluded. The Review Manager (Version 5.4) was utilised in data analysis. RESULTS: A total of 25,199 post-TAVR patients with AF were included from seven articles, with 9764 patients on non-vitamin K antagonist oral anticoagulants (NOAC) and 15,435 patients on vitamin K antagonists (VKA). In this analysis, there was a significantly lower risk of all-cause mortality at 1 year (RR: 0.75, CI: 0.58-0.97, p = 0.04, I2 = 56%), and bleeding at 1 year (RR: 0.73, CI: 0.68-0.79, p = < 0.00001, I2 = 0%), between patients on NOAC and VKA. There were no detectable differences between patients on NOAC and VKA for all-cause mortality at 2 years, stroke within 30 days, stroke within 1 year, ischaemic stroke at 1 year and life-threatening bleeding at 30 days. CONCLUSION: While the results of this analysis reveal NOAC as a potential alternate treatment modality to VKA in post-TAVR patients with AF, further research is needed to determine the full safety and efficacy profile of NOAC (PROSPERO: CRD42021283548).

What Does It Take to Become an Academic Plastic Surgeon in Canada: Hiring Trends Over the Last 50 Years.

Objective: Academic plastic surgery positions have become highly competitive secondary to delayed retirement, stagnant hospital funding, and an increasing number of plastic surgery graduates. Little information is available to help residents navigate this challenging landscape. Our objectives were to evaluate the training backgrounds of all Canadian academic plastic surgeons and to develop recommendations for residents interested in an academic career. Methods: All Canadian academic plastic surgeons were included. Training histories were obtained from institutions' websites. Surgeons were subsequently emailed to confirm this information and complete missing details. Multivariate regressions were designed to analyze the effect of gender and FRCSC year on graduate and fellowship training and time to first academic position. Results: Training information was available for 196 surgeons (22% female), with a 56% email response rate; 91% of surgeons completed residency in Canada; 94% completed fellowship training, while 43% held graduate degrees; 74% were employed where they previously trained. Female gender significantly lengthened the time from graduation to first academic job, despite equal qualification. Younger surgeons were more likely to hold graduate degrees (P < .01). Conclusions: We identified objective data that correlate with being hired at an academic centre, including training at the same institution, obtaining a graduate degree during residency, and pursuing fellowship training. In addition, we demonstrated that women take significantly longer to acquire academic positions (P < .01), despite equal qualification. Trainees should consider these patterns when planning their careers. Future research should explore gender-based discrepancies in hiring practices.

Objectif: Les postes universitaires en chirurgie plastique sont hautement convoités en raison des retraites reportées, du gel du financement des hôpitaux et d'un nombre grandissant de diplômés en chirurgie plastique. Il y a peu d'information visant à aider les résidents à s'y retrouver dans ce contexte difficile. Nos objectifs consistaient à évaluer la formation de tous les chirurgiens plasticiens universitaires au Canada et de mettre au point des recommandations à l'intention des résidents souhaitant mener une carrière universitaire. Méthodologie: Tous les chirurgiens plasticiens universitaires du Canada ont été inclus. L'historique de formation a été obtenue auprès des sites Web des établissements. On a ensuite fait parvenir aux chirurgiens un courriel visant à confirmer ces renseignements et à compléter l'information manquante. Des régressions multifactorielles ont été conçues pour analyser l'effet du sexe et de l'année d'obtention du titre FRCSC sur l'accès à la formation aux cycles supérieurs et l'octroi des bourses de formation, ainsi que sur le délai précédant le moment où les chirurgiens plasticiens décrochent leur premier poste universitaire. Résultats: Les renseignements sur la formation étaient disponibles pour 196 chirurgiens (dont 22 % de sexe féminin), et le taux de réponse par courriel a été de 56 %. Quatre-vingt-onze pour cent des chirurgiens ont terminé leur résidence au Canada. Quatre-vingt-quatorze pour cent des chirurgiens avaient reçu une bourse de formation, tandis que quarante-trois pour cent détenaient des diplômes d'études supérieures. Soixante-quatorze pour cent des chirurgiens sont devenus des employés de l'établissement où ils avaient déjà suivi une formation. À compétences égales, les chirurgiens de sexe féminin tardaient beaucoup plus à décrocher un premier emploi universitaire après l'obtention de leur diplôme que ceux de sexe masculin. Plus les chirurgiens étaient jeunes, plus ils étaient susceptibles de détenir un diplôme d'études supérieures (p < 0,01). Conclusions: Nous avons obtenu des données objectives présentant une corrélation avec l'embauche dans un centre universitaire, y compris une formation au même établissement, l'obtention d'un diplôme d'études supérieures durant la résidence et le maintien d'une bourse de formation. En outre, nous avons montré que même à compétences égales, les femmes prennent beaucoup plus de temps à décrocher des postes universitaires (p < 0,01). Les étudiants doivent tenir compte de ces profils dans leur planification de carrière. Des recherches futures devront explorer les écarts entre les sexes pour ce qui est des pratiques d'embauche.

Chronic Consumption of Cranberries (Vaccinium macrocarpon) for 12 Weeks Improves Episodic Memory and Regional Brain Perfusion in Healthy Older Adults: A Randomised, Placebo-Controlled, Parallel-Groups Feasibility Study.

Background: Ageing is highly associated with cognitive decline and modifiable risk factors such as diet are believed to protect against this process. Specific dietary components and in particular, (poly)phenol-rich fruits such as berries have been increasingly recognised for their protection against age-related neurodegeneration. However, the impact of cranberries on cognitive function and neural functioning in older adults remains unclear. Design: A 12-week parallel randomised placebo-controlled trial of freeze-dried cranberry powder was conducted in 60 older adults aged between 50 and 80 years. Cognitive assessment, including memory and executive function, neuroimaging and blood sample collection were conducted before and after the intervention to assess the impact of daily cranberry consumption on cognition, brain function and biomarkers of neuronal signalling. Results: Cranberry supplementation for 12 weeks was associated with improvements in visual episodic memory in aged participants when compared to placebo. Mechanisms of action may include increased regional perfusion in the right entorhinal cortex, the accumbens area and the caudate in the cranberry group. Significant decrease in low-density lipoprotein (LDL) cholesterol during the course of the intervention was also observed. No significant differences were, however, detected for BDNF levels between groups. Conclusions: The results of this study indicate that daily cranberry supplementation (equivalent to 1 small cup of cranberries) over a 12-week period improves episodic memory performance and neural functioning, providing a basis for future investigations to determine efficacy in the context of neurological disease. This trial was registered at clinicaltrials.gov as NCT03679533 and at ISRCTN as ISRCTN76069316.

Living in a Region With a Low Level of COVID-19 Infection: Health Belief Toward COVID-19 Vaccination and Intention to Receive a COVID-19 Vaccine in Hong Kong Individuals.

INTRODUCTION: Vaccination is vital for controlling the COVID-19 pandemic. Individuals' vaccination intention is a good predictor of vaccine uptake and is influenced by individuals' health belief toward vaccination. Regions with different levels of pandemic severity may present varying effects. This study aimed to determine the influence of health belief on COVID-19 vaccination intention in a region with a low level of COVID-19 infection. METHODS: This cross-sectional telephone survey was conducted on a quota sample of 800 adults in Hong Kong before the commencement of the local COVID-19 vaccination program. The Health Belief Model Scale-COVID-19 was developed to assess health belief toward COVID-19 vaccination. The contribution of health belief on explaining intention to receive the COVID-19 vaccine was assessed using logistic regression. RESULTS: The subjects demonstrated moderate levels in all aspects of health belief. Only 28.9% of the subjects indicated an intention to receive a COVID-19 vaccine. After controlling for age, educational level, marital status, and high risk status, the logistic regression analysis indicated that perceived benefits of vaccination (OR = 1.615; CI 95%: 1.443-1.807; P < .001), perceived susceptibility to COVID-19 (OR = 1.130; CI 95%: 1.032-1.237; P = .008), cues to action toward vaccination (OR = 1.212; CI 95%: 1.108-1.326; P < .001), and perceived barriers to vaccination (OR = .696; CI 95%: .641-.756; P < .001) were associated with intention to receive a COVID-19 vaccine. CONCLUSION: Vaccination campaigns in regions with good control of the pandemic should promote the benefits of vaccination, emphasizing how it can help individuals regain a sense of normalcy in their daily lives and stop the spread of COVID-19. Although the COVID-19 pandemic affects countries worldwide, this study highlights the importance of adopting specific vaccination promotion strategies for regions with different levels of pandemic severity.

Impact of the COVID-19 Pandemic on the Wellness of Canadian Plastic Surgery Residents.

On top of preexisting burnout, depression, and anxiety among trainees, the COVID-19 pandemic has introduced novel stressors. The objectives of this study were to determine the effects of the COVID-19 pandemic on Canadian plastic surgery residents' practice, wellness, and overall training. Methods: Surveys for program directors and residents were created and disseminated to all English-speaking Canadian plastic surgery residency training programs. Survey results were pooled and presented as a percentage of responses for each question. Results: Response rates were 50% (n = 5/10) and 25% (n = 19/77) for program directors and residents, respectively. All program directors believed that the pandemic has a negative effect on resident wellness, 80% (n = 4/5) of which believed that their residents were coping effectively. They rated program support for resident wellness as neutral or supportive. Most programs (80%; n = 4/5) introduced strategies to support resident well-being. Most trainees (84%; n = 16/19) reported the pandemic as having a negative effect on their well-being, with approximately 50% endorsing worse emotional, social, psychological, and physical wellness, as well as feelings of burnout. Some reported difficulties coping (21%; n = 4/19). Residents felt that their wellness was supported externally by their own resilience (89%; n = 17/19), family members (74%; n = 14/19), friends (74%; n = 14/19), their partner (68%; n = 13/19), or co-residents (53%; n = 10/19). Internal support by their program was rated as neutral or negative (63%; n = 12/19). Conclusions: Our findings of negative effects of the COVID-19 pandemic on the wellness of Canadian plastic surgery trainees are concerning. Programs must implement appropriate identification and support strategies to improve resident well-being.

Can epigenetics shine a light on the biological pathways underlying major mental disorders?

A significant proportion of the global burden of disease can be attributed to mental illness. Despite important advances in identifying risk factors for mental health conditions, the biological processing underlying causal pathways to disease onset remain poorly understood. This represents a limitation to implement effective prevention and the development of novel pharmacological treatments. Epigenetic mechanisms have emerged as mediators of environmental and genetic risk factors which might play a role in disease onset, including childhood adversity (CA) and cannabis use (CU). Particularly, human research exploring DNA methylation has provided new and promising insights into the role of biological pathways implicated in the aetio-pathogenesis of psychiatric conditions, including: monoaminergic (Serotonin and Dopamine), GABAergic, glutamatergic, neurogenesis, inflammatory and immune response and oxidative stress. While these epigenetic changes have been often studied as disease-specific, similarly to the investigation of environmental risk factors, they are often transdiagnostic. Therefore, we aim to review the existing literature on DNA methylation from human studies of psychiatric diseases (i) to identify epigenetic modifications mapping onto biological pathways either transdiagnostically or specifically related to psychiatric diseases such as Eating Disorders, Post-traumatic Stress Disorder, Bipolar and Psychotic Disorder, Depression, Autism Spectrum Disorder and Anxiety Disorder, and (ii) to investigate a convergence between some of these epigenetic modifications and the exposure to known risk factors for psychiatric disorders such as CA and CU, as well as to other epigenetic confounders in psychiatry research.

Outcomes of Management of Recurrent Dupuytren Contracture: A Systematic Review and Meta-analysis.

BACKGROUND: With numerous treatment modalities available, it is unclear whether the treatment of recurrent Dupuytren disease is as effective as its initial treatment. We aimed to investigate the outcomes of management of recurrent Dupuytren contracture. METHODS: Adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, MEDLINE, Embase, PubMed, CINAHL, and Cochrane Central Register of Controlled Trials were searched from their inception to April 2020. Studies of patients aged above 18 years undergoing treatment for recurrent Dupuytren contractures were included. The Risk Of Bias In Non-randomized Studies-of Interventions tool was used for quality assessment. The study was registered with Open Science Foundation. RESULTS: A systematic review identified 12 studies: 311 patients with 224 affected digits-index (n = 5; 2.2%), long (n = 17; 7.6%), ring (n = 57; 25.4%), small (n = 112; 50%), and unspecified (n = 33; 14.7%); of these, there were 76 metacarpophalangeal joints (MCPJ; 45.5%), 90 proximal phalangeal joints (PIPJ; 53.9%), and 1 distal interphalangeal joint (0.6%). Previous treatment included the following: percutaneous needle aponeurotomy (n = 103 of 311 patients; 33.1%), collagenase clostridium histolyticum-injection (CCH; n = 75 of 311; 24.1%), limited fasciectomy (LF) ± skin graft (n = 83 of 311; 26.7%), fasciotomy (n = 1 of 311; 0.3%), and unspecified (n = 64 of 311; 20.6%). Recurrence was treated by percutaneous needle aponeurotomy (n = 68 of 311 patients; 21.9%); CCH injection (n = 53 of 311; 17.0%); aponeurotomy or dermofasciectomy or LF (n = 176 of 311; 56.6%); ray/digit amputation (n = 8 of 311; 2.6%); and PIPJ arthrodesis (n = 6 of 293; 2.0%). Range of motion was improved by 23.31° (95% confidence interval [CI] = 13.13°-33.50°; I2 = 67%; P = .05) and 15.49° (95% CI = 2.67°-28.31°; I2 = 76%; P = .01) for MCPJ and PIPJ, respectively. CONCLUSIONS: There is low level of evidence that both surgical and nonsurgical treatments provide clinically important improvements for recurrent Dupuytren contracture.

Topographic Evolution of Anterior Cerebral Artery Infarction and Its Impact on Motor Impairment.

INTRODUCTION: Motor deficit is common following anterior cerebral artery (ACA) stroke. This study aimed to determine the impact on the motor outcome, given the location of descending corticofugal fiber tracts (from the primary motor cortex [M1], dorsal and ventral premotor area [PMdv], and supplementary motor area [SMA]) and the regional variations in collateral support of the ACA territory. METHODS: Patients with ACA vessel occlusion were included. Disruption to corticofugal fibers was inferred by overlap of tracts with a lesion on computed tomography perfusion at the onset and on magnetic resonance imaging (MRI) poststroke. The motor outcome was defined by dichotomized and combined National Institute of Health Stroke Scale (NIHSS) sub-scores for the arm and leg. Multivariate hierarchical partitioning was used to analyze the proportional contribution of the corticofugal fibers to the motor outcome. RESULTS: Forty-seven patients with a median age of 77.5 (interquartile range 68.0-84.5) years were studied. At the stroke onset, 96% of patients showed evidence of motor deficit on the NIHSS, and the proportional contribution of the corticofugal fibers to motor deficit was M1-33%, SMA-33%, and PMdv-33%. By day 7, motor deficit was present in <50% of patients and contribution of M1 fiber tracts to the motor deficit was reduced (M1-10.2%, SMA-61.0%, PMdv-28.8%). We confirmed our findings using publicly available high-resolution templates created from Human Connectome Project data. This also showed a reduction in involvement of M1 fiber tracts on initial perfusion imaging (33%) compared to MRI at a median time of 7 days poststroke (11%). CONCLUSION: Improvements in the motor outcome seen in ACA stroke may be due to the relative sparing of M1 fiber tracts from infarction. This may occur as a consequence of the posterior location of M1 fiber tracts and the evolving topography of ACA stroke due to the compensatory capacity of leptomeningeal anastomoses.

Anterior Cerebral Artery Stroke: Role of Collateral Systems on Infarct Topography.

Background and Purpose: The circle of Willis (CoW) and leptomeningeal anastomoses play an important role in transforming infarct topography following middle cerebral artery occlusion. Their role in infarct topography following anterior cerebral artery occlusion is not well understood. The aim of this study was to evaluate the role of the CoW and leptomeningeal anastomoses in modifying regional variation in infarct topography following occlusion of the anterior cerebral artery and its branches. Methods: Perfusion and magnetic resonance imaging of patients with anterior cerebral artery stroke and evidence of vessel occlusion were segmented and manually registered to standard brain template for voxel-wise comparison. Next, a computer model of the cerebral arteries was formulated as network of nodes connected by cylindrical pipes. The experiments included occlusion of successive branches of the anterior cerebral artery while the configurations of the CoW were varied. Results: Forty-seven patients with a median age of 77.5 years (interquartile range, 68.0­84.5 years) were studied. The regions with the highest probabilities of infarction were the superior frontal gyrus (probability =0.26) and anterior cingulate gyrus (probability =0.24). The regions around the posterior cingulate gyrus (probability =0.08), paracentral lobule (probability =0.05), precuneus and superior parietal lobule (probability =0.03) had a low probability of infarction. Following occlusions distal to the anterior communicating artery, the computer model demonstrated an increase in flow (>30%) in neighboring cortical arteries with leptomeningeal anastomoses. Conclusions: Traditionally the CoW has been regarded as the primary collateral system. However, our computer model shows that the CoW is only helpful in redirecting flow following proximal vessel occlusions (pre-anterior communicating artery). More important are leptomeningeal anastomoses, which play an essential role in distal vessel occlusions, influencing motor outcome by modifying the posterolateral extent of infarct topography.

Glucagon-Like Peptide-1 Receptor Agonists for Non-Alcoholic Fatty Liver Disease in Type 2 Diabetes: A Meta-Analysis.

Objective: Non-alcoholic fatty liver disease is highly prevalent in patients with type 2 diabetes mellitus. Studies on glucagon-like peptide-1 receptor agonists for the treatment of non-alcoholic fatty liver disease have reported promising results. Despite this, there has been limited evidence of its efficacy in non-alcoholic fatty liver disease patients with type 2 diabetes mellitus. This meta-analysis examined existing evidence on the efficacy of glucagon-like peptide-1 receptor agonists on the management of non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus. Methods: Medline, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for articles discussing the efficacy of glucagon-like peptide-1 receptor agonists on non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus. Values of standardized mean differences (SMD) and risk ratio (RR) were determined for continuous outcomes and dichotomous outcomes respectively. Results: 8 studies involving 1,454 patients from 5 randomized controlled trials and 3 cohort studies were included in the analysis. Our analysis found significant improvements in hepatic fat content, liver biochemistry, body composition, glucose parameters, lipid parameters, insulin sensitivity and inflammatory markers following glucagon-like peptide-1 receptor agonist treatment. Glucagon-like peptide-1 receptor agonists significantly decreased hepatic fat content compared to metformin and insulin-based therapies. Glucagon-like peptide-1 receptor agonists also improved fibrosis markers, but this did not reach statistical significance. Conclusion: With a high prevalence of obesity and non-alcoholic fatty liver disease among patients with type 2 diabetes mellitus, glucagon-like peptide-1 receptor agonist treatment shows promise in improving both diabetes and non-alcoholic fatty liver disease phenotype.

Astrocyte-mediated purinergic signaling is upregulated in a mouse model of Fragile X syndrome.

Fragile X syndrome (FXS) is the leading monogenic cause of intellectual disability and autism spectrum disorders. With increasing investigation into the molecular mechanisms underlying FXS, there is growing evidence that perturbations in glial signaling are widely associated with neurological pathology. Purinergic signaling, which utilizes nucleoside triphosphates as signaling molecules, provides one of the most ubiquitous signaling systems for glial-neuronal and glial-glial crosstalk. Here, we sought to identify whether purinergic signaling is dysregulated within the FXS mouse cortex, and whether this dysregulation contributes to aberrant intercellular communication. In primary astrocyte cultures derived from the Fmr1 knockout (KO) mouse model of FXS, we found that application of exogenous ATP and UTP evoked elevated intracellular calcium responses compared to wildtype levels. Accordingly, purinergic P2Y2 and P2Y6 receptor expression was increased in Fmr1 KO astrocytes both in vitro and in acutely dissociated tissue, while P2Y antagonism via suramin prevented intracellular calcium elevations, suggesting a role for these receptors in aberrant FXS astrocyte activation. To investigate the impact of elevated purinergic signaling on astrocyte-mediated synaptogenesis, we quantified synaptogenic protein TSP-1, known to be regulated by P2Y activation. TSP-1 secretion and expression were both heightened in Fmr1 KO vs wildtype astrocytes following UTP application, while naïve TSP-1 cortical expression was also transiently elevated in vivo, indicating increased potential for excitatory TSP-1-mediated synaptogenesis in the FXS cortex. Together, our results demonstrate novel and significant purinergic signaling elevations in Fmr1 KO astrocytes, which may serve as a potential therapeutic target to mitigate the signaling aberrations observed in FXS.

High Prevalence and Mechanism Associated With Extended Spectrum Beta-Lactamase-Positive Phenotype in Laribacter hongkongensis.

In this study, we reported the prevalence and mechanism associated with the extended-spectrum beta-lactamase (ESBL)-positive phenotype in Laribacter hongkongensis isolated from patients and fish. Using the inhibition zone enhancement test, 20 (95.2%) of the 21 patient strains and 8 (57.1%) of the 14 fish strains were tested ESBL-positive. However, ESBL genes, including SHV, TEM, CTX-M, GES, and PER, were not detected in all of these 28 L. hongkongensis isolates. No ESBL gene could be detected in either the complete genome of L. hongkongensis HLHK9 or the draft genome of PW3643. PCR and DNA sequencing revealed that all the 35 L. hongkongensis isolates (showing both ESBL-positive and ESBL-negative phenotypes) were positive for the ampC gene. When the AmpC deletion mutant, HLHK9ΔampC, was subject to the zone enhancement test, the difference of zone size between ceftazidime/clavulanate and ceftazidime was less than 5 mm. When boronic acid was added to the antibiotic disks, none of the 28 "ESBL-positive" isolates showed a ≥ 5 mm enhancement of inhibition zone size diameter between ceftazidime/clavulanate and ceftazidime and between cefotaxime/clavulanate and cefotaxime. A high prevalence (80%) of ESBL-positive phenotype is present in L. hongkongensis. Overall, our results suggested that the ESBL-positive phenotype in L. hongkongensis results from the expression of the intrinsic AmpC beta-lactamase. Confirmatory tests should be performed before issuing laboratory reports for L. hongkongensis isolates that are tested ESBL-positive by disk diffusion clavulanate inhibition test.